CA-125 Response Research Articles

Oral Metronomic Therapy: An Effective Palliative Treatment Option for Epithelial Ovarian Cancer.

Introduction The majority of the patients with advanced-stage epithelial ovarian cancer relapse within three years of standard first-line treatment. Access to novel therapies like poly ADP-ribose polymerase (PARP) inhibitors and antiangiogenic agents is limited in low- and middle-income countries. Oral metronomic therapy (OMT) may be an effective alternative treatment option in resource-limited settings. Materials and methods A retrospective study was conducted among patients with epithelial ovarian cancer who received OMT. OMT consisted of cyclophosphamide 50mg per day and tamoxifen 40mg per day which was administered continuously until unacceptable toxicity or progression was reached. OMT was given to patients with relapsed ovarian cancer and to those newly diagnosed ovarian cancer patients who were unfit for cytoreductive surgery and/or standard first-line intravenous platinum-based chemotherapy. All patients who received OMT at our center between 01-01-2017 and 31-12-2021 were included for analysis. Relevant details, as needed for the study, were collected from medical records. SPSS version 24 (IBM Corp., Armonk, NY) was used for statistical analysis. Results A total of 61 patients received OMT during the study period. The median age at diagnosis of ovarian cancer was 59 years. The median age at the start of OMT was 61 years. The majority (n= 37, 60.7%) had high-grade serous carcinoma subtype. A total of 52 patients received OMT in the relapse setting while nine received it in the first-line setting. Among relapsed ovarian cancer patients, 13 patients (21.3%) experienced platinum-sensitive relapse, 16 patients (26.2%) experienced partial platinum-sensitive relapse, and 23 patients (37.7%) experienced platinum-resistant disease. The mean duration of treatment with OMT was 7.8 months. The clinical benefit rate was 59% and the overall response rate was 22.9%. Ca-125 response was seen in 40.4% of patients. The median PFS for the overall group was 6.7 months. Median PFS was longer in patients with Ca-125 response and platinum-sensitive relapse. Only five patients (8.1%) had significant toxicity. Conclusion OMT is a safe and effective palliative treatment option for epithelial ovarian cancer, worth consideration in low- and middle-income countries.

Acupuncture and Related Therapies for Endometriosis: A Network Meta-Analysis of Randomized Controlled Trials.

Acupuncture and related therapies are effective and safe ways to relieve the pain, and improve the health and quality of life in women with endometriosis-related pain. However, it is still unclear which treatment is the most effective. Our study aims to summarize the evidence and determine the most effective and safe method to treat the endometriosis. We searched PubMed, EMBASE, Cochrane Library, and Web of science, China Biology Medicine, China National Knowledge Infrastructure, Wan fang Data, Chinese Scientific Journal Database and conducted manual searches of relevant papers, summarized randomized clinical trials of acupuncture-related therapies for endometriosis from database inception to 21 April 2024. After independent literature screening and data extraction that pain VAS was selected as the primary outcome measure. The quality evaluation was conducted by Review Manager 5.4. Perform network meta-analysis (NMA) used Stata 15.0 software. Forty-two eligible trials involving six acupuncture-related interventions and 3,635 participants were included in this NMA. Pairwise meta-analyses show that combination therapy was more efficacious than western medicine and Chinese herb medicine for pain VAS scores, serum CA125 level and response rate results. The NMA estimates indicated that: for pain VAS scores, acupuncture (SMD: -2.33; 95% CI: -4.37, -0.29) and combination therapy (SMD: 1.79 95% CI: 1.21, 2.41) were superior to western medicine. For serum CA125 level, acupoint application (SMD: -11.33 95% CI: -20.28, -2.97) and combination therapy (SMD: 6.20; 95% CI: 1.60, 10.75) were associated with better efficacy when considered alongside western medicine. For response rate, combination therapy (SMD: 0.20; 95% CI: 0.14, 0.29) and auricular therapy (SMD: 8.01; 95% CI: 2.08, 45.37) were more efficacious than western medicine. The comprehensive ranking results show that acupoint catgut embedding was the best performing at lowering pain VAS scores, acupoint application was identified as the most effective in reducing serum CA125 level, and auricular therapy was ranked first in improving the response rate. Acupoint catgut embedding, auricular therapy, acupoint application and combination therapy may be the best solutions for the treatment of endometriosis. Additional trials are needed to develop higher-quality evidence and optimal regimens.

Real-life clinical benefit of oral metronomic cyclophosphamide administration in elderly and heavily pretreated epithelial ovarian cancer patients

PurposeOral metronomic cyclophosphamide (OMC) implicates the daily administration of low doses of chemotherapy. Its antitumor activity combined with an oral administration route and a good toxicity profile makes OMC an attractive option for heavily pretreated patients. We retrospectively evaluated OMC’s clinical benefit and objective response in recurrent ovarian cancer patients.MethodsThis is a retrospective observational study involving patients treated with OMC (50 mg daily) from 2017 to 2022 at the Academic Division Gynaecology, Mauriziano Hospital, Torino, Italy. Clinical benefit assessment included CA125 response, radiological response, and reported symptomatic improvement. Toxicities were reported using Common Terminology Criteria for Adverse Events version 5.0.ResultsThirty-eight patients (average age 72, range 49–88) were included. 90% had FIGO stage III/IV at diagnosis and 64% underwent ≥ 3 previous lines of chemotherapy. Before OMC, 79% had ECOG 1 or 2. 8.6% of patients had a partial response (PR), and 40% a stable disease (SD). Median duration of response was 7.4 months. After 3 months on OMC, 51% experienced symptom improvement, and 53.3% experienced Ca125 reduction or stabilization. 66.7% of patients older than 75 responded to treatment; in 40% of cases, responses lasted ≥ 6 months (p = 0.08). No G3-4 hematological toxicities occurred. Nausea and fatigue G1–G2 were reported in 5 (13%) and 13 (34%) cases, respectively.ConclusionOMC is a feasible therapeutic option for recurrent ovarian cancer, providing satisfying clinical responses with a good toxicity profile, even in elderly and heavily pretreated patients with a suboptimal performance status.

Gynecologic Cancer InterGroup CA125 response has a high negative predictive value for CHK1 inhibitor RECIST response in recurrent ovarian cancer

We investigated the association of CA125 response with prognosis and RECIST response/progressive disease (PD) criteria in recurrent high grade serous ovarian cancer (HGSOC) patients treated with a cell cycle checkpoint kinase 1 inhibitor (CHK1i), prexasertib. 81 patients had measurable disease per RECISTv1.1, of which 72 and 70 were measurable by Gynecologic Cancer InterGroup (GCIG) CA125 response and PD criteria, respectively. Univariate and multivariate analyses showed that GCIG CA125 response (n = 32) is associated with improved progression-free survival (PFS) and overall survival (OS) compared to no GCIG CA125 response (n = 40) (median PFS 8.0 vs. 3.5 months [HR: 0.30, 95% CI: 0.18–0.51, p < 0.0001]; median OS 19.8 vs. 10.0 months [HR: 0.38, 95% CI: 0.23–0.64, p < 0.001]) independent of BRCA mutation status, platinum-sensitivity, previous PARP inhibitor therapy, ECOG performance status, and FIGO stage. Notably, GCIG CA125 response had a high negative predictive value (NPV: 93%, 95% CI: 80–98), but poor positive predictive value (PPV: 53%, 95% CI: 35–71) in predicting RECIST response. CA125 PD criteria also showed poor concordance with RECIST PD (PPV 56%, 95% CI: 40–71; NPV 33%, 95% CI: 17–54). Therefore, serum CA125 may be useful as a highly accessible prognostic and predictive biomarker to CHK1i therapy in recurrent HGSOC.

Use of Gynecologic Cancer Intergroup (GCIG) CA125 criteria to evaluate cell cycle checkpoint kinase 1 inhibitor (CHK1i) prexasertib response and disease progression (PD) in recurrent high-grade serous ovarian cancer (HGSOC).

e17536 Background: Data suggest discordance between serum biomarker CA125 and Response Evaluation Criteria in Solid Tumors (RECIST) response and/or PD in chemotherapies and PARP inhibitors. Here, we investigated the impact of CA125 on prognosis and its relationship with RECIST response/PD in HGSOC patients treated with a CHK1i, prexasertib. Methods: All relapsed HGSOC patients in this post-hoc analysis were treated with prexasertib at 105 mg/m2 IV every 14 days in a 28-day cycle until RECIST v1.1 PD, unacceptable toxicity, or consent withdrawal (NCT02203513). CA125 was assessed every cycle and CT scans obtained every two cycles. GCIG CA125 response was defined as &gt;50% reduction confirmed after 28 days and PD as &gt; 2X upper limit of normal (ULN) if baseline was normal or doubling of nadir if baseline was elevated. Patients with baseline CA125 &lt; 2X ULN or nadir &gt; 750 units/mL were not eligible for analysis. Clinical benefit rate (CBR; CR + PR + SD ≥ 6 months) was analyzed by Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier curves and univariate (UV) and multivariate (MV) hazard ratios by Cox regression models. Positive predictive value (PPV) and negative predictive value (NPV) confidence intervals (CI) were estimated by the Wilson-Brown method. Results: Eighty-one patients received at least two cycles of prexasertib between January 2015 and November 2020, out of which 72 were evaluable by both RECIST and GCIG CA125 response criteria. CBR in the CA125 response (CA125-R) group (24/32; 75%) was significantly higher than the CA125 non-responder (CA125-N) group (12/40; 30%; p&lt;0.001). CA125 response tended to occur prior to RECIST response (median: 28 days; IQR: 28, 30). PFS was improved in CA125-R at 8.0 months vs. CA125-N at 3.5 months (UV HR: 0.34, 95% CI: 0.21-0.56; MV HR: 0.35, 95% CI: 0.20-0.59). OS was improved in CA125-R at 19.8 months vs. CA125-N at 10.3 months (HR: 0.43, 95% CI: 0.26-0.71; MV HR: 0.45, 95% CI: 0.27-0.75). No significant differences in PFS or OS were observed between subgroups by BRCA mutation status, platinum-sensitivity, FIGO stage, baseline CA125 value, or previous PARP inhibitor therapy in MV analysis. Out of 70 patients evaluable by RECIST and CA125 PD criteria, 43 patients had CA125 PD and 24 of those had RECIST PD occur within one cycle of CA125 PD (PPV: 59%; 95% CI: 43-72). Of the 27 patients without a CA125 PD, 9 patients also did not have a RECIST PD (NPV: 33%; 95% CI: 19-52). Conclusions: GCIG CA125 response is an independent predictor of response to CHK1i in HGSOC prior to the first restaging scans and is associated with a higher CBR and improved PFS and OS. However, GCIG CA125 PD has poor PPV and NPV within a one cycle window, indicating that CA125 alone is not sufficient in monitoring for PD in HGSOC treated with CHK1i.

Study on the efficacy and toxicity of pamiparib combined with tamoxifen in the treatment of patients with epithelial ovarian cancer with biochemical recurrence during first-line PARPi maintenance therapy.

TPS5621 Background: A high proportion of ovarian cancer patients tend to have elevated CA-125 1-6 months before imaging recurrence. The time between biochemical recurrence (i.e., only elevated CA-125 without imaging finding or clinical symptoms) to imaging recurrence can be considered a "window period", and if the “window period” can be extended, it may convert platinum-resistant relapsed patients to platinum-sensitive patients, and ultimately improving patient outcomes. The timing of treatment for the biochemical recurrent patients has been controversial. Tamoxifen, an anti-estrogenic drug, is considered an effective option for these patients. Pamiparib (BGB-290) is an investigational small molecule inhibitor of PARP1 and PARP2. According to OReO study(NCT03106987), the "PARPi after PARPi" strategy is effective in recurrent ovarian cancer patients previously treated with a PARP inhibitor. Therefore, we aim to further explore the use of PARP inhibitors in maintenance therapy for patients with ovarian cancer. Methods: This study (NCT05669768) will evaluate the efficacy and toxicity of pamiparib and tamoxifen in ovarian cancer patients with biochemical recurrence during first-line PARPi maintenance therapy. The included ovarian cancer patients are required to achieve No Evidence of Disease (NED) or demonstrated a response following platinum-based chemotherapy, with normalized CA-125 levels. First-line maintenance treatment with a PARP inhibitor is mandatory, with a minimum interval of ≥6 months to biochemical recurrence. The trial design is interventional, employing a Simon two-stage design to estimate sample size. The primary outcome of the study is the CA-125 response rate, which was assessed according to the GCIG criteria.1 The secondary outcome was Time to First Subsequent Therapy (TFST). Patients undergo regular assessments for tumor markers and imaging throughout treatment. If persistent elevation of tumor markers or the detection of recurrent lesions or distant metastases is observed, the patient is promptly removed from the study group. Standardized antitumor therapy is then initiated based on the patient's condition. The total planned enrollment is 46 participants, utilizing a single-group assignment and an open-label design. 1 of planned 12 patients for the first stage of accrual have been enrolled. Reference: 1. Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21(2):419-423. Clinical trial information: NCT05669768 .

Abstract CT042: NCI10217: Phase Ib biomarker-driven tumor-agnostic combination (Combo) trial of copanlisib (Copa) and olaparib (Ola) in molecularly-selected patients (pts) with advanced cancers with PIK3CA hotspot, PTEN and DNA damage response (DDR) mutations

Abstract Background: Preclinically, PI3K and PARP inhibition synergize in cancers with DDR and PI3K pathway alterations. NCI10217 assessed the combo of Copa (pan-PI3K inhibitor) and Ola (PARP inhibitor) in tumors harboring mutations in PI3K/AKT or DDR pathways. Materials and Methods: Eligible pts had tumors with pathogenic PIK3CA hotspot, PTEN and DDR mutations. Copa was administered at 45 mg to 60 mg IV on Days (D) 1 and 15 or 1, 8 and 15 with Ola at 200 mg to 300 mg twice daily (BID) orally in 28-days cycles. Prior PARP and PI3K inhibitors were permitted. Fresh tumor biopsies and ctDNA were mandated at baseline and C1D15 and optional at the end of trial. Study objectives were safety, RP2D, pharmacokinetics, antitumor activity and translational analyses of serial tumor (WES; RNA-Seq; RPPA) and ctDNA samples. Results: 28 pts (M:F 8:20; ECOG PS 0:1 9:19; mean age 58y (28-76y) with breast (n=6), colorectal (n=5), prostate (n=4), endometrial (n=2), gastric (n=2), vaginal (n=2), appendix, cervix, head and neck, leiomyosarcoma, ovarian, peritoneal, and renal (n=1) cancers were enrolled. Pts with BRCA1/2 (n=12), PTEN (n=10), PIK3CA hotspot (n=6), ARID1A (n=4), CHEK2 (n=3), PALB2 (n=3), ATM (n=2), CDK12, CHEK1, MRE11A, RAD51C (n=1 each) mutations were enrolled. 10 pt tumors harbored &amp;gt;1 qualifying mutation. 17 (61%)/28 pts had ≥3 prior lines of therapy; 2 (7%)/28 had prior PARP inhibitors and 1 (4%)/28 had prior PI3K inhibitor. Common treatment-related toxicities included G1/2 mucositis (43%), nausea (43%), diarrhea (36%), anorexia (29%), fatigue (29%), maculo-papular rash (29%), hyperglycemia (25%), vomiting (25%); G3 transient hypertension (29%). Dose-limiting toxicities occurred in 3 (11%)/28 pts: 1 pt (G3 elevated transaminases) at Copa 45 mg (D1, D8 and D15) + Ola 200 mg BID, and 2 pts (G2 mucositis and maculo-papular rash, and G4 hyperglycemia) at Copa 60 mg (D1, D8, and D15) + Ola 300 mg BID. Of 22 pts evaluable for RECISTv1.1 criteria, 6 (27%)/22 pts achieved RECISTv1.1 partial responses (PR): 2 pts with BRCA1 mutation breast cancer; 1 pt with PIK3CA + PTEN + ARID1A mutation breast cancer; 1 pt with PTEN + PALB2 mutation breast cancer and prior PARP inhibitor exposure; 1 pt with BRCA2 mutation prostate cancer; 1 pt with BRCA2 + PTEN mutation prostate cancer. 8 (36%)/22 pts achieved RECISTv1.1 stable disease (SD); 2 (25%)/8 pts had SD≥6 months, including a pt with CA125 response (&amp;gt;50% reduction). Clinical benefit rate (SD≥6 months + PR) was 36%. Responses were deep (up to -100%) and durable (up to 37+ months). Based on these data, the RP2D was established at Copa 60 mg D1 and D15 + Ola 300 mg BID. Conclusion: Copa + Ola was safe and well-tolerated with clinical benefit observed in 36% of pts with advanced cancers with PIK3CA hotspot, PTEN and/or DDR mutations. Translational analyses are ongoing. Citation Format: Timothy A. Yap, Ecaterina E. Dumbrava, Jordi Rodon Ahnert, Apostolia M. Tsimberidou, David Hong, Sarina A. Piha-Paul, Daniel D. Karp, Siqing Fu, Aung Naing, Paula Pohlmann, Jessica R. Rhudy, Sheila B. Berenji-Jalaei, Ashley A. Cole, Christian Valladolid, Desirae Dufner, Bruno B. Bockorny, Andrea Bullock, Daniel Fein, Elizabeth Buchbinder, Atish Choudhury, Candace Haddox, Elizabeth Lee, Gerburg Wulf, Percy Ivy, Rabih Said, Geoffrey Shapiro, Funda Meric-Bernstam. NCI10217: Phase Ib biomarker-driven tumor-agnostic combination (Combo) trial of copanlisib (Copa) and olaparib (Ola) in molecularly-selected patients (pts) with advanced cancers with PIK3CA hotspot, PTEN and DNA damage response (DDR) mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT042.

Abstract A083: Personalized targeted circulating tumor DNA (ctDNA) and T-cell responses after combined neoantigen vaccine and immune checkpoint blockade in ovarian cancer

Abstract A083: Personalized targeted circulating tumor DNA (ctDNA) and T-cell responses after combined neoantigen vaccine and immune checkpoint blockade in ovarian cancer

Abstract A077: The utility of surgical minimal residual disease after frontline treatment for prognostic and investigational opportunities in advanced ovarian cancer

Abstract Cure rates for patients with advanced stage ovarian cancer have not changed significantly over the last four decades likely due to inability to eradicate residual cancer cells after frontline therapy. Identifying clinically undetectable minimal residual disease (MRD) after frontline therapy by second look laparoscopy (SLL) has potential to a) uncover mechanisms of chemoresistance and tumor dormancy, b) identify MRD-specific therapeutic targets, and c) allow for earlier intervention with investigational therapies. The objective of this study is to describe the initial safety and feasibility of SLL and illustrate clinical and pathological correlates. Methods: This IRB-approved observational, single-center study includes patients with epithelial high-grade ovarian cancer with complete CA-125 and radiologic response after frontline treatment (combination of surgery and platinum-taxane chemotherapy) who underwent SLL from 4/2017-6/2023. Patients were subsequently offered standard of care or investigational maintenance therapy options based on homologous recombination deficiency (HRD) and MRD status. Summary statistics described the study population, chi-square tests compared categorical variables, and progression free survival (PFS) based on MRD status was estimated using Kaplan-Meier method and compared using log rank test. Results: 70 patients underwent SLL with a median of 8.5 biopsies (range 3-16). The majority of patients had stage III-IV disease (90%), and high-grade serous histology (90%). Approximately half (51.4%) of patients underwent neoadjuvant chemotherapy (NACT) with interval tumor reductive surgery (TRS). MRD was present in 32 patients (45.7%), and the presence of MRD was associated with a worse PFS (HR 3.0, 95% CI 1.5-5.8; 12.5 vs. 24.8 months; p=0.001). MRD was more frequent among NACT recipients compared to those who underwent primary TRS (63% vs 26%, P=0.002), those with HRD negative tumors (58% vs 24%, P=0.025), and those with R1 versus R0 resections (71% vs 39%, P=0.024). Of patients with MRD, 22 patients (71%) received bevacizumab until progression as part of a clinical trial (NCT02884648), 3 (10%) received bevacizumab off trial, 5 (16%) received a PARP inhibitor (all HRD positive), and 1 received other therapy. There were two (2.9%) intraoperative complications (both enterotomies) requiring conversion to laparotomy. Conclusions: SLL is feasible, overall safe, and detected MRD in 46% of ovarian cancer patients who were in radiologic and CA-125 remission after frontline therapy. PFS was significantly shorter for patients with residual disease, despite those patients all receiving additional therapy. Knowledge of MRD status in this patient population enables interventional, observational, and translational opportunities, as well as personalized prognostic counseling. MRD rate may also have utility as an early surrogate for efficacy in trials evaluating novel frontline investigational therapies. Future studies will compare the performance of circulating tumor DNA (ctDNA) versus surgical MRD. Citation Format: Anne Knisely, Roni Nitecki, J. Alejandro Rauh-Hain, R. Tyler Hillman, Jolyn S. Taylor, Lois M. Ramondetta, Michaela O. Grinsfelder, Lauren P. Cobb, David M. Boruta, Gwyn Richardson, Pamela T. Soliman, Aaron Shafer, Shannon N. Westin, Nicole D. Fleming, Travis T. Sims, Anil K. Sood, Pedro T. Ramirez, Karen H. Lu, Amir A. Jazaeri. The utility of surgical minimal residual disease after frontline treatment for prognostic and investigational opportunities in advanced ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A077.

Abstract B045: Ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in combination with low dose gemcitabine in patients with solid tumors with DNA damage response (DDR) aberrations: Preclinical and Phase 1b results

Abstract Background: Antitumor activity and good tolerability of camonsertib (cam) monotherapy in patients (pts) with recurrent solid tumors was previously reported. Preclinical data showed that cam-related tumor cell death is potentiated by the replication stress-inducing agent gemcitabine (gem) even at low doses, resulting in synergistic combination activity. We evaluated safety/tolerability and efficacy of cam+gem in this Ph1b trial (TRESR; NCT04497116). Methods: A tumor xenograft (Granta-519; ATM loss of function) was tested with a range of cam+gem doses. Pts &amp;gt;18yr, ECOG 0-1, with advanced solid tumors with deleterious DDR alterations were enrolled. Cam (80-120mg) + de-escalating gem doses (1000-100mg/m2) were given over 21- or 28-day (d) cycles (cam d1-2/3 and d8-9/10 or d15-16/17; gem d1 and d8 or d15). Dose decisions followed BOIN methodology. Endpoints were safety/tolerability, recommended Ph2 dose (RP2D), response rate (RECIST v1.1, CA-125 [GCIG], or PSA [PCWG3]), clinical benefit rate (CBR; response or treatment [Tx] duration ≥16 weeks [w] without progression), ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency ≥50%), and cam PK. Replication stress markers were analyzed in surrogate normal tissue. Results: In a tumor xenograft model, low doses of cam (1/3 of maximum tolerated dose [MTD]) and gem (1/20 of MTD) resulted in tumor regression not observed in single agent arms, with good tolerability. As of May 2023, 54 pts were treated with cam+gem in TRESR (ovarian [n=19], pancreatic [n=8], breast [n=6], other [n=21] tumors); enrollment genes included ATM (n=12), BRCA1 (n=18), BRCA2 (n=16), other (n=8). No drug-drug interactions were noted. RECIST v1.1 or CA-125 responses were observed in 5 pts (40 evaluable): 3 cPR, 1 uPR in pts with ovarian (n=2; 1 ATM, 1 BRCA1), endometrial (gPALB2), and breast (gBRCA1) cancers; 1 CA-125 response in a pt (ovarian/gBRCA1) with SD (on Tx 21w+). Four additional pts (uterine carcinosarcoma, ovarian, liver, lung) with SD were on Tx ≥6 months. CBR was 42.4% (14/33) in evaluable pts and 66.7% (8/12) in pts with gynecological cancers. MRR was 58% (7/12) in evaluable pts. Myelotoxicity, the most frequent Tx-related toxicity, improved with decreasing gem doses. Responses were maintained in the 3 pts with cPR following reductions to ≤200mg/m2 gem; the pts with the uPR and CA-125 responses started Tx at 200 and 100mg/m2 gem, respectively. Preliminary RP2D is 80mg cam (50% of monotherapy RP2D) + 400mg/m2 gem, 28d cycle (1w on/1w off). Related Grade 3+ neutropenia, anemia, and thrombocytopenia occurred in 44%, 11%, and 0% pts, respectively (n=9). Importantly, neutrophil nadir occurred in the 1w off Tx with quick rebound, alleviating the need for dose modifications. Conclusion: The synergy of low doses of cam+gem, demonstrated in preclinical studies, was confirmed in the clinical setting. A safe and tolerable dose and schedule of the combination was identified. The antitumor efficacy supports further development in pts with gynecological cancers; evaluation at RP2D is ongoing. Citation Format: Ezra Rosen, Timothy A Yap, Elisa Fontana, Elizabeth K Lee, Devalingam Mahalingam, Martin Højgaard, Niharika B Mettu, Gregory M Cote, Ruth Plummer, Ian M Silverman, Joseph D Schonhoft, Emeline Bacque, Adrian J Fretland, Gabriela Gomez, Danielle Ulanet, Kezhen Fei, Julia Yang, Maria Koehler, Anne Roulston, Li Li, Michal Zimmermann, Benedito A Carneiro, Stephanie Lheureux. Ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in combination with low dose gemcitabine in patients with solid tumors with DNA damage response (DDR) aberrations: Preclinical and Phase 1b results [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B045.

Abstract PR008: MYTHIC: First-in-human (FIH) biomarker-driven phase I trial of PKMYT1 inhibitor lunresertib (lunre) alone and with ATR inhibitor camonsertib (cam) in solid tumors with CCNE1 amplification or deleterious alterations in FBXW7 or PPP2R1A

Abstract Background: Lunre (RP-6306), a first-in-class membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase (PKMYT1) inhibitor, disrupts G2/M checkpoint causing DNA damage in cells with synthetic lethal alterations. Lunre plus the ATR inhibitor cam (RP-3500) promotes premature mitosis via CHK1/Cdc25 regulation and tumor regression. The FIH phase 1 MYTHIC trial assessed lunre alone or in combo with cam (lunre + cam) (NCT04855656). Methods: Pts &amp;gt;12yrs with advanced solid tumors and CCNE1 amplification, or deleterious FBXW7 or PPP2R1A mutations received oral lunre alone (QD or BID) or lunre (QD or BID) + cam (QD) continuously or intermittently using BOIN design. Endpoints: safety, tolerability, RP2D, preliminary efficacy (RECIST v1.1, GCIG CA-125), clinical benefit rate (CBR; RECIST/GCIG CA-125 or therapy duration ≥16w), ctDNA molecular response, PK and PD. Results: As of June 1, 2023, 108 pts were treated; n=66 lunre alone; n=42 lunre + cam. Tumors: uterine (31.5%), colorectal (20.4%), ovarian (16.7%), others (31.5%); median 3 prior therapies. 39.8% had CCNE1, 36.1% FBXW7, 19.4% PPP2R1A, and 4.6% had 2 or no alterations. Treatment-related AEs for lunre alone vs lunre + cam: nausea/vomiting (31.8% vs 64.3%; G3 1.5% vs 0%), anemia (21.2% vs 64.3%; G3 7.6% vs 38.1%), rash (34.8% vs 31%; G3 7.6% vs 2.4%), fatigue (22.7% vs 38.1%; G3 1.5% vs 0%). Lunre DLTs included G2/3 rash reversible with drug holds +/- supportive care. Preliminary RP2Ds: (1) lunre alone 100mg BID 5 days (d) on/2d off or 240mg QD continuous; (2) lunre 80mg BID + cam 80mg QD, both 3d on/4d off. Lunre exhibited linear PK up to daily doses ~240mg with ~9h half-life. No lunre + cam drug-drug interaction was observed. Target engagement (CDK1-Thr14 IHC) was confirmed in paired tumor biopsies treated with lunre alone (p=0.001; n=17) and with cam (p=0.039; n=11). DNA damage induction (gH2AX) was observed across both treatment groups (p=0.013; n=36). ctDNA molecular responses were achieved in 10/18 pts (55.6%) on lunre + cam. For lunre alone, 1 pt with uterine carcinosarcoma/PPP2R1A &amp; FBXW7 had RECIST PR. For lunre + cam, among evaluable pts, 8 had either RECIST response (confirmed or unconfirmed; n=6: bile duct/CCNE1, breast/FBXW7, CRC/FBXW7, endometrial/FBXW7, PPP2R1A &amp; CCNE1, or PPP2R1A &amp; FBXW7) or CA-125 response (n=2: ovarian/CCNE1), including 5/15 pts (33.3%) with endometrial/ovarian cancers; CBR was 43.2% in all pts, and 66.7% in pts with endometrial/ovarian cancers. Conclusion: Lunre is safe and well-tolerated with robust PK/PD proof-of-mechanism. Antitumor responses or durable clinical benefit was observed in tumors with CCNE1, FBXW7, and PPP2R1A alterations at biologically active doses of lunre + cam, especially in gynecological cancers. These data provide the first clinical proof-of-concept for synthetic lethal targeting of PKMYT1 in cancer medicine. Dose optimization and efficacy expansions are ongoing. Trial registration number: NCT04855656 Citation Format: Timothy A Yap, Alison Schram, Elizabeth K Lee, Fiona Simpkins, Mia C Weiss, Patricia LoRusso, Martin Højgaard, Benedito A Carneiro, Ryan H Moy, Ignacio Garrido-Laguna, Maria Koehler, Thaddeus J Unger, Emeline Bacque, Elia Aguado-Fraile, Sunantha Sethuraman, Snehal Dhake, Yajun Liu, Adrian J Fretland, Xizi Sun, Yi Xu, Nathan Hawkey, Jen Truong, Stephanie Lheureux. MYTHIC: First-in-human (FIH) biomarker-driven phase I trial of PKMYT1 inhibitor lunresertib (lunre) alone and with ATR inhibitor camonsertib (cam) in solid tumors with CCNE1 amplification or deleterious alterations in FBXW7 or PPP2R1A [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR008.

Pegylated liposomal doxorubicin and carboplatin versus paclitaxel and carboplatin as first-line treatment for Chinese patients with ovarian cancer: A multi-center, randomized, open-label trial.

5556 Background: Paclitaxel combined with carboplatin is a standard first-line chemotherapy regimen for ovarian cancer. This study was designed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin (CD) compared with paclitaxel plus carboplatin (CP) as first-line treatment for epithelial ovarian cancer (EOC). Methods: Patients with stage IC to IV EOC, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this open-label, randomized controlled trial at 20 centers in China. Patients were randomly assigned 1:1 to CD group (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m2) or CP group (carboplatin AUC 5 plus paclitaxel 175 mg/m2) every 3 weeks for 3-6 cycles. The primary end point was progression free survival (PFS); secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Between March, 2019 to December, 2021, 395 patients were enrolled, of whom 391 patients were analyzed (195 assigned to CD, 196 to CP). Baseline characteristics were balanced between the two treatment groups. The median follow-up was 21.6 months for the CD group and 22.5 months for the CP group. There was no significant difference in PFS between the two arms (P=0.516); the median PFS was 28.1 months and 30.1 months in the CD and CP arms, respectively. OS data were immature at data cutoff, with a total of 26 deaths in the two treatment groups. In patients with at least one measurable lesion at baseline, ORR was 65.5% in the CD arm and 66.2% in the CP arm (P= 0.941); DCR was 74.1% and 73.8% in the CD and CP arms, respectively (P= 0.971). Among patients who were evaluable by GCIG CA125 criteria, CA125 response was obtained in 86.0% and 88.5% of patients in the CD and CP arms, respectively (P=0.560). More frequent grade 1 to 3 alopecia (32.1% vs 12.3%) and neurotoxicity (20.4% vs 0%) were observed in the CP arm; more hand-foot syndrome (grade 1 to 3, 10.8% vs 2.6%), and oral mucositis (grade 1-3, 12.8% vs 5.1%) in the CD arm. Conclusions: The efficacy of CD regimen is comparable to that of CP, with less alopecia and neurotoxicity. CD may be an alternative first-line treatment for EOC. However, survival data are not yet mature, and longer follow-up is needed. Clinical trial information: NCT03794778 .

Utility of surgically documented minimal residual disease as a therapeutic target and early surrogate of frontline treatment outcomes in ovarian cancer.

5549 Background: Cure rates for patients with advanced stage ovarian cancer have not changed over the last four decades likely due to inability to eradicate residual cancer cells after frontline therapy. Identifying clinically undetectable minimal residual disease (MRD) after frontline therapy by second look laparoscopy (SLL) has potential to a) uncover mechanisms of chemoresistance, b) identify MRD-specific therapeutic targets, and c) allow for earlier intervention with investigational therapies. The objective of this study is to describe the initial safety and feasibility of SLL and illustrate clinical pathologic correlates. Methods: This IRB-approved observational, single-center study includes patients with epithelial high-grade ovarian cancer with complete CA-125 and radiologic response after frontline treatment who underwent SLL from 4/2017-12/2022. Patients were subsequently offered standard of care or investigational maintenance therapy options based on homologous recombination deficiency (HRD) and MRD status. Summary statistics described the study population, chi-square tests compared categorical variables, and progression free survival (PFS) based on MRD status was estimated using Kaplan-Meier method and compared using log rank test. Results: 64 patients underwent SLL with a median of 8 biopsies (range 1-16). The majority of patients had stage III-IV disease (89%), and high-grade serous histology (89%). Approximately half (52%) of patients underwent neoadjuvant chemotherapy (NACT) with interval tumor reductive surgery (TRS). MRD was present in 28 patients (44%), and the presence of MRD was associated with a worse PFS (HR 3.1, 95% CI 1.5-6.3; 9.2 vs 24.6 months; P=0.002). MRD was more frequent among NACT recipients compared to those who underwent primary TRS (61% vs 26%, P=0.005), those with HRD negative tumors (63% vs 22%, P=0.003), and those with R1 versus R0 resections (71% vs 35%, P=0.012). Of patients with MRD, 20 patients (71%) received bevacizumab until progression as part of a clinical trial (NCT02884648), 3 (11%) received bevacizumab off trial, 4 (14%) received a PARP inhibitor (all HRD positive) and 1 received other therapy. There was one (1.6%) intraoperative complication requiring conversion to laparotomy. Conclusions: SLL is feasible, overall safe, and detected MRD in 44% of ovarian cancer patients who were in radiologic and CA-125 remission after frontline therapy. MRD rates were higher in patients who received NACT and HRD negative patients, and PFS was significantly longer in patients without residual disease. MRD rate by SLL may have utility as an early surrogate for efficacy in trials evaluating novel frontline investigational therapies. Knowledge of MRD status in this patient population enables interventional, observational, and translational investigations, as well as personalized prognostic counseling.

Abstract CT227: Interim results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody®) monotherapy and in combination with toripalimab (an anti-PD-1 antibody) in patients (pts) with advanced/metastatic solid tumors

Abstract Background: ADG126 is an anti-CTLA-4 fully human IgG1 SAFEbody® with a masking peptide blocking the antigen binding site. ADG126 is designed to be preferentially activated in the tumor microenvironment (TME), with the goal of limiting on-target off-tumor toxicities and promoting prolonged exposure to active drug in the TME. Activated ADG126 binds to a unique and conserved epitope of CTLA-4 with species cross-reactivity. Nonclinical studies have demonstrated that activated ADG126 potentiates T cell activation and depletes immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC) specifically in the TME. We present interim results from our ongoing Phase 1b/2 study (ADG126-1001, NCT04645069) on dose escalation and expansion of ADG126 monotherapy as well as dose escalation of ADG126 + toripalimab (Tori). Method: Pts with advanced solid tumors received ADG126 monotherapy (0.1, 0.3, 1, 3, 10, and 20 mg/kg) Q3W IV or ADG126 (6 or 10 mg/kg) + Tori (240mg) Q3W IV. Primary endpoints are safety and tolerability. Secondary endpoints are PK, anti-drug antibody (ADA), as well as ORR, DCR, DOR and PFS per RECIST 1.1. Result: As of Dec. 26, 2022, 30 pts have received ADG126 monotherapy. The median number of treatment cycles was 2 (range: 1-24). The median age was 63.5 (39-84) years. 43% of pts had ≥ 3 prior lines of therapies, and 47% had been previously treated with anti-PD-(L)1 and/or anti-CTLA-4 therapies. ADG126 was well-tolerated with no dose-limiting toxicities (DLTs) observed, nor was the MTD reached. Only Grade (G) 1-2 TRAEs were reported; TRAEs ≥10% included diarrhea (17%), fatigue (17%), pruritus (13%), and rash (10%). Among 27 evaluable pts, DCR = 37%. One pt with ovarian serous carcinoma had a major CA125 response (90% reduction) and her disease was stable with ongoing treatment of ADG126 1 mg/kg at Cycle 24 (~16 months). In addition, 14 pts have received ADG126 + Tori in the dose escalation cohorts. The median age was 60 (36-85) years; 50% had ≥ 3 prior lines of therapies, and 43% received prior anti-PD-1 therapies. Both dose levels were well tolerated with no DLT. TRAEs (&amp;gt; 10%) included diarrhea (21%), fatigue (14%), pruritus (14%), rash (14%) and nausea (14%). After multiple cycles at 6 or 10 mg/kg Q3W, G3 TRAEs were observed in 21% (3/14) pts, including elevated liver function test/hepatitis, elevated lipase and diarrhea, which are immune-related, and sepsis. No G4/5 TRAEs have been reported. Among 12 evaluable pts, DCR = 58%, including 2 partial responses. Early efficacy signals were observed with continuous tumor shrinkage and stabilization in IO-resistant and cold tumors. Conclusion: The anti-CTLA-4 SAFEbody ADG126 shows favorable safety profiles in monotherapy up to 20 mg/kg and in combination with Tori up to 10 mg/kg. Furthermore, promising anti-tumor activity in heavily pre-treated patients was observed in the dose escalation phase. By enabling higher dose levels in combination with anti-PD-1 therapy, ADG126 may unleash the full therapeutic potential for proven and novel indications. Citation Format: Mihitha Ariyapperuma, John J. Park, Adnan Khattak, Gary Richardson, Anis Hamid, Michelle Morris, Anthony W. Tolcher, Boon Cher Goh, Justina Lam, Bartosz Chmielowski, Kristine She, Yanyan Zhang, Ai Li, Songmao Zheng, Guizhong Liu, Lvyu Zhu, Hongyan Wang, Xiaoxing Cui, Peter Luo, Jiping Zha. Interim results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody®) monotherapy and in combination with toripalimab (an anti-PD-1 antibody) in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT227.

Abstract 5610: [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-inhibitor drug-target engagement as a biomarker of response in ovarian cancer

Abstract Purpose: Poly(ADP-ribose) polymerase enzyme inhibitors (PARPi) have become the standard-of-care treatment for homologous recombination deficient (HRD) high-grade serous ovarian cancer (HGSOC). However, not all HRD tumors respond to PARPi and biomarkers to predict response are needed. [18F]FluorThanatrace (FTT) is a PARPi-analog PET radiotracer that non-invasively measures PARP-1 expression. Herein, we evaluate the ability of FTT uptake to serve as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and patients with HGSOC. Patients and Methods: In PDX models, FTT-PET was performed before and after PARPi (olaparib), ataxia-telangiectasia inhibitor (ATRi), or both. Changes in FTT were correlated with tumor size changes. Patients with HRD and HGSOC that were enrolled in CAPRI (PARPi+ATRi), LIGHT (PARPi only), or off-trial (PARPi only) were selected for this single-center, prospective, cohort, IRB-approved study. FTT-PET/CT imagining was obtained from the skull base to the proximal thighs on an Ingenuity TF scanner (Philips Healthcare) 60-90 minutes after intravenous infusion of 8-12 mCi FTT. Subjects were imaged with FTT-PET at baseline and after ~1 week of PARPi monotherapy treatment. Target lesions (primary tumor and/or metastases) were identified at the time of the baseline imaging on correlative anatomic imaging using RECIST 1.1 and maximum standardized uptake value (SUVmax) data, normalized by body weight, was collected. Changes in FTT-PET uptake were compared to changes in tumor size, CA-125, and progression free survival (PFS). Results: A decrease in FTT tumor uptake after 1 week of PARPi treatment correlated with response to PARPi+ATRi treatment in PARPi-resistant PDX models (r=0.81-0.83, P=0.1-0.22). In HGSOC patients (n=13), percent differences in FTT-PET after ~7 days of PARPi compared to baseline correlated with the first RECIST response (r=0.60, P=0.034), best RECIST response (r=0.75, P=0.01), best CA-125 response (r=0.73, P=0.033), and PFS (r=0.67, P=0.027). All patients with &amp;gt;50% reduction in FTT uptake had &amp;gt;6-month PFS and &amp;gt;50% reduction in CA-125 (P=0.004 and P=0.016, respectively). Utilizing only baseline FTT uptake correlated to best RECIST response (r=-0.65, P=0.035) but did not predict response when corelated with other measures. Importantly, a decrease in FTT uptake does not appear to be associated with a reduction in tumor burden or apoptosis in response to drug cytotoxic activity at this early timepoint, indicating specificity for drug-target engagement. Conclusions: The decline in FTT uptake shortly after PARPi initiation compared to baseline provides an in vivo measure of drug-target engagement and shows promise as an early biomarker to guide PARPi therapy. FTT-PET has both pre-clinical and clinical applications warranting further study, including guiding PARPi combination therapy. Citation Format: Sarah B. Gitto, Austin R. Pantel, Mehran Makvandi, Hyoung Kim, Sergey Medvedev, Joanna K. Weeks, Drew A. Torigian, Chia-Ju Hsieh, Benjamin Ferman, Nawar A. Latif, Janos L. Tanyi, Lainie P. Martin, Shannon M. Lanzo, Fang Liu, Quy Cao, Gordon B. Mills, Robert K. Doot, David A. Mankoff, Robert H. Mach, Lilie L. Lin, Fiona Simpkins. [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-inhibitor drug-target engagement as a biomarker of response in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5610.

Tumor immune microenvironment changes are associated with response to neoadjuvant chemotherapy and long-term survival benefits in advanced epithelial ovarian cancer: A pilot study.

Little is known about the association between efficacy of neoadjuvant chemotherapy (NACT)/survival and the dynamic change of tumor immune environment (TIME) during treatment in epithelial ovarian cancer (EOC). This study investigated the TIME landscape of treatment-naive EOC tumors using multiplex immunofluorescence and associated the TIME before and after platinum-based NACT with treatment efficacy and prognosis in 33 patients with advanced EOC. NACT significantly increased the density of CD8+ T cells (P = 0.033), CD20+ B cells (P = 0.023), CD56 NK cells (P = 0.041), PD-1+ cells (P = 0.042), and PD-L1+CD68+ macrophages (P = 0.005) in the tissue specimens. Response to NACT was evaluated using CA125 response and chemotherapy response score (CRS). Compared with the non-responders, the responders displayed a larger proportion of tumors showing increase in the infiltration of CD20+ cells (P = 0.046) and in the M1/M2 ratio (P = 0.038) as well as fewer tumors showing increase in the infiltration of CD56bright cells (P = 0.041). No association was found between pre-NACT TIME and response to NACT. Density of pre-NACT CD8+ cells was positively associated with longer progression-free survival (PFS) (P = 0.011) and overall survival (OS) (P = 0.048). Post-NACT CD20+ and CD163+ macrophages (M2) infiltrates were associated with prolonged (P = 0.005) and shortened PFS (P = 0.021), respectively. Increase in the density of CD4+ T cells was predictive for longer PFS (P = 0.022) and OS (P = 0.023). In the multivariate analysis, high density of CD8+ cells pre-NACT (P = 0.042) were independently associated with improved OS.

Phase II Trials of Iniparib (BSI-201) in Combination with Gemcitabine and Carboplatin in Patients with Recurrent Ovarian Cancer.

Iniparib (BSI-201), a novel anticancer agent thought to have poly(ADP-ribose) polymerase (PARP) inhibitory activity and synergy with both gemcitabine and carboplatin (GC) was evaluated in 2 cohorts with GC. Parallel multicenter, single-arm, phase II studies using a Simon two-stage design. Eligible patients had a histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma and demonstration of platinum-sensitive (≥6 months [mo]) or -resistant disease (relapse 2-6 mo post-platinum). Carboplatin (AUC 4 IV day 1), gemcitabine (1000 mg/m2 IV days 1 and 8), and iniparib (5.6 mg/kg IV days 1, 4, 8, and 11) were given on a 21-day cycle. The overall response rate (ORR RECIST 1.0) in platinum sensitive disease was 66% (95% CI, 49-80) with a higher response rate in the 15 pts with germline BRCA mutations (gBRCAmut) (73%). Median PFS was 9.9 (95% CI, 8.2-11.3) months. In the platinum resistant population the ORR was 26% (95% CI, 14-42), however in the 11 pts for whom BRCA mutation was present, the best overall response was PR in 5 (46%). Median PFS was 6.8 months (range, 5.7-7.7 months). Notably, among the 17 CA-125-response-evaluable patients who did not achieve tumor response, 7 (41.2%) patients had a CA125 response, and 93% has clinical benefit (CR + PR + SD). The GCI combination was generally well tolerated despite a high incidence of thrombocytopenia and neutropenia, with no new toxicities. Given the subsequent lack of efficacy demonstrated for iniparib in breast cancer, these are studies of GC and demonstrate a higher than traditionally appreciated activity in patients with platinum-sensitive and -resistant recurrent ovarian cancer, especially in patients that harbor a BRCA mutation, resetting the benchmark for efficacy in phase II trials. (ClinicalTrials.gov Identifiers: NCT01033292 & NCT01033123).

PICCOLO: An open-label, single arm, phase 2 study of mirvetuximab soravtansine in recurrent platinum sensitive, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate-alpha (FRα) expression (300)

Objectives: Elevated FRα expression is a characteristic of epithelial ovarian cancer (EOC), thereby providing an attractive candidate for targeted therapeutic approaches. Mirvetuximab soravtansine is an antibody-drug conjugate (ADC) comprising an FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has consistently shown clinically meaningful single-agent activity, along with favorable tolerability, in patients with high FRα expressing tumors (Moore ESMO 2019). Methods: PICCOLO is a single-arm, phase II study designed to evaluate the efficacy of mirvetuximab soravtansine in adult patients with recurrent platinum-sensitive EOC (including primary peritoneal cancer, or fallopian tube cancer) who would be, in the opinion of the investigator, candidates for a non-platinum, single-agent therapy for their next line of therapy. Confirmation of high FRα positivity by immunohistochemistry using the Ventana FOLR1CDx Assay (high expression; ≥ 75% of cells with PS2+ staining intensity) and two prior lines of platinum-based therapy are required for inclusion. Patients with a documented platinum allergy require only one prior line of platinum. PICCOLO will enroll 75 patients who will receive intravenous mirvetuximab soravtansine at a dose of 6 mg/kg, calculated using adjusted ideal body weight, on Day 1 of a 21-day cycle. The primary efficacy endpoint is objective response rate (ORR; by investigator) and secondary endpoints include duration of response, progression-free survival, overall survival, CA-125 response, and safety and tolerability. PICCOLO is a global study that opened for enrollment in August 2021. Clinical trial information: NCT05041257. Objectives: Elevated FRα expression is a characteristic of epithelial ovarian cancer (EOC), thereby providing an attractive candidate for targeted therapeutic approaches. Mirvetuximab soravtansine is an antibody-drug conjugate (ADC) comprising an FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has consistently shown clinically meaningful single-agent activity, along with favorable tolerability, in patients with high FRα expressing tumors (Moore ESMO 2019). Methods: PICCOLO is a single-arm, phase II study designed to evaluate the efficacy of mirvetuximab soravtansine in adult patients with recurrent platinum-sensitive EOC (including primary peritoneal cancer, or fallopian tube cancer) who would be, in the opinion of the investigator, candidates for a non-platinum, single-agent therapy for their next line of therapy. Confirmation of high FRα positivity by immunohistochemistry using the Ventana FOLR1CDx Assay (high expression; ≥ 75% of cells with PS2+ staining intensity) and two prior lines of platinum-based therapy are required for inclusion. Patients with a documented platinum allergy require only one prior line of platinum. PICCOLO will enroll 75 patients who will receive intravenous mirvetuximab soravtansine at a dose of 6 mg/kg, calculated using adjusted ideal body weight, on Day 1 of a 21-day cycle. The primary efficacy endpoint is objective response rate (ORR; by investigator) and secondary endpoints include duration of response, progression-free survival, overall survival, CA-125 response, and safety and tolerability. PICCOLO is a global study that opened for enrollment in August 2021. Clinical trial information: NCT05041257.

Tissue is the issue: Chemotherapy response score (CRS) is most predictive of response to neoadjuvant chemotherapy in advanced, high grade serous ovarian cancer (HGSOC) (488)

Tissue is the issue: Chemotherapy response score (CRS) is most predictive of response to neoadjuvant chemotherapy in advanced, high grade serous ovarian cancer (HGSOC) (488)

Abstract 6106: The effect of neoadjuvant chemotherapy on tumor immune microenvironment in ovarian cancer

Abstract Background: Ovarian cancer (OC) is a highly lethal gynecologic malignancy, neoadjuvant chemotherapy (NACT) with interval de-bulking surgery (IDS) is an established strategy for woman with advanced epithelial ovarian cancer (EOC). Tumor infiltrating lymphocytes (TILs) play an important role in the pathogenesis of OC. However, the effect of NACT on tumor immune microenvironment (TIME) has not been evaluated. Methods: All patients underwent NACT with IDS. Formalin-fixed paraffin-embedded tissue samples were collected from biopsy specimens and the corresponding post-NACT surgical specimens. The densities and percentage of specific TILs [CD8+, CD3+, CD4+, CD20+, tumor associated macrophages (TAMs), dim CD56+NK, bright CD56+NK, PD-1+ etc.] within the TIME were analyzed by multiplex immunohistochemistry (3DMedcines Inc.). Serum CA 125 was measured 3-weekly per protocol and evaluated the response to NACT using GCIG CA125 response criteria. Results: A total of 28 patients were enrolled in this study with planned IDS after NACT. Of 25 patients evaluated by GCIG CA125 response criteria, 76% (19/25) had a CA125 response. In CA125 response patients, we observed significant recruitments of the densities and percentage of CD8+ in tumor, percentage of PD-1+ cell in tumor after-NACT vs before-NACT (34.85/mm3 vs 110.54/mm3, p=0.0258; 0.50% vs 1.73%, p=0.0132; 0.53% vs 2.66%, p=0.0576, respectively), while no significant change was found in TAMs, NK cells and CD20+ cells. However, in CA125 non-response patients, the TILs in tumor did not change significantly. Conclusion: NACT could release the tumor associated antigen by killing tumor cells for uptake by tumor-infiltrating dendritic cells and promote the infiltration of CD8+ and PD-1+ T lymphocyte in CA125 response OC patients. Given the limited clinical prognostic information and the number of patients in this study, the results of this study will need confirmation in larger studies in the future. Citation Format: Guangming Cao, Dingchao Hua, Lina Cui, Xiaochen Zhao, Shuzhen Wang, Lei Zhu. The effect of neoadjuvant chemotherapy on tumor immune microenvironment in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6106.